Ghrelin mitigates ß-cell mass loss during insulitis in an animal model of autoimmune diabetes mellitus, the BioBreeding/Worcester rat.

BACKGROUND: Ghrelin is a peptide hormone with pleiotropic effects. It stimulates cell proliferation and inhibits apoptosis-mediated cell death. It prevents diabetes mellitus in several models of chemical, surgical and biological toxic insults to pancreas in both in vivo and in vitro models and promotes glucose-stimulated insulin secretion under cytotoxic conditions. It has not yet been tested in vivo in an autoimmune model of diabetes with a persistent insult to the ß-cell. Given the immunomodulating effects of ghrelin and its trophic effects on ß-cells, we hypothesized that ghrelin treatment during the early stages of insulitis would delay diabetes onset. METHODS: BioBreeding/Worcester male rats received ghrelin (10 ng/kg/day) before insulitis development. Glucose metabolism was characterized by glucose and insulin tolerance tests. ß-cell mass, islet area, islet number, ß-cell clusters, proliferation and apoptosis and degree of insulitis were analysed by histomorphometry. A Kaplan-Meier survival curve was plotted and analysed applying the log-rank (Mantel-Cox) test. RESULTS: Ghrelin treatment significantly reduced the probability of developing diabetes in our model (p < 0.0001). It decreased islet infiltration and partially prevented ß-cell mass loss, enabling the maintenance of ß-cell neogenesis and proliferation rates. Furthermore, ghrelin treatment did not induce any metabolic perturbations. CONCLUSIONS: These findings support the hypothesis that ghrelin delays the development of autoimmune diabetes by attenuating insulitis and supporting ß-cell mass. GENERAL SIGNIFICANCE: Ghrelin promotes ß-cell viability and function through diverse mechanisms that may have significant implications for diabetes prevention, therapy and also transplant success of both islets and complete pancreas. Copyright © 2016 John Wiley & Sons, Ltd.